Rats are an important experimental model for many human diseases, many of which have a genetic component. As another approach to investigating fundamental origins of autoimmune diseases, we have initiated studies with the ultimate goal of mapping genes regulating autoimmune disease in rats. A initial and critical step to meet this objective is the development of a genetic linkage map applicable to autoimmune-disease prone and -resistant rat strains. Over the past year, we have identified more than 300 new polymorphic DNA markers that distinguish various inbred rat strains (total of about 900 since the initiation of the project). We have now mapped a large fraction of these markers in F2 progeny of LEW x F344 (more than 400 markers total), LEW x BN (more than 400 markers), or DA x F344 (about 200 markers). The genetic map that we have developed has been used the refine our previous localization of the rat athymic nude trait on rat chromosome 10. We have also now refined our localization of the rat osteopetrosis gene (op) to the distal end of rat chromosome 10. Several efforts are in progress to map phenotypes related to autoimmune disease in F2 progeny of LEW X F344 rats. In addition, we are mapping genes that regulate collagen-induced arthritis (CIA), an autoimmune disease model that resembles rheumatoid arthritis, in F2 progeny of DA x F344 rats. Over the past year, we have generated data in the LEW X F344 progeny indicating that virtually all of the phenotypes under investigation are subject to complex regulation involving 2-4 genes in distinct chromosomal locations. In the CIA model, we have identified a major regulatory locus (LOD approximately 63), linked to the major histocompatibility complex (MHC) on chromosome 20. This locus acts dominantly and contributes approximately 50% to the phenotypic variability. In addition, at least 4, and possibly 5, additional chromosomal regions (chromosomes 1,4,7 and 14) contribute to phenotypic variability. The mode of action of the non-MHC genes is still being analyzed.